A single replacement of beta 6 glutamic acid residue in each of the two beta chains of hemoglobin (Hb) A by a valine residue in Hb S should have only a local effect on the conformation of the beta chains near the N-terminals. It is proposed that the first turn of the helix A in the beta chains is unwound and residues beta 1 to beta 6 of one Hb S molecule contacts the unordered region of residues beta 77 to beta 84 of another Hb S molecule, which is close to beta 73 residue in the last turn of helix E of the beta chains. These contacts are probably stabilized by one or more intermolecular hydrogen bonds and also side group interactions (an ideal beta-form with maximum hydrogen bonds is not a necessary requirement). The aggregation proceeds in both directions leading to the formation of single filaments, followed by lateral aggregation into 6-stranded fibers and the gelation of sickle- cell hemoglobins. The validity of this hypothesis will be tested by synthesizing oligo- and polypeptides which mimic portions of the amino acid sequence of the Hb molecule. These compounds are expected to compete for the binding sites between the Hb S molecules and thus interfere with their gelation. The minimum gelling concentration of Hb S will be determined under various conditions (concentration of oligopeptides, ionic strength, pH and temperature). Ideally, some of these oligopeptides may turn out to be anti-sickling agents.